Plastics container containing stabilized drug formulation

ABSTRACT

A plastics container containing a sterile aqueous solution of an acid addition salt of a 1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecaboxamide, wherein the solution is buffered.

FIELD OF THE INVENTION

This invention relates to a new drug formulation, and in particular tobags, ampoules or other containers including a sterile drug solution.

BACKGROUND OF THE INVENTION

Many drugs are provided in aqueous solution. For this purpose, they aretypically packaged, in a glass, plastics or other container such as anampoule, vial or bag, and sterilised by autoclaving. They can then bestored and used as necessary.

One class of drugs that is administered as a solution, e.g. by injectionor infusion, comprises the long-acting local anesthetics which includean amine. Particular examples of this type of therapeutic agent are1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamides, of whichspecific examples are mepivacaine, ropivacaine, bupivacaine andlevobupivacaine. These drugs are usually provided as the hydrochloridesalt.

Jones et al, Am. J. Hosp. Path. 50(11):2364-5 (1993), reports that therewere no significant changes in assay or pH upon storage of bupivacainein polypropylene syringes.

Similarly, Upton etat, Aus. J. Hosp. Pharm. 17(4): 267-70 (1987),demonstrated no adsorption of bupivacaine to a range of plasticsinducing polypropylene.

Hampe Da Poian et al, Revista Brasileira de Anestesiologia 33(1):23-5(1983), reported no significant changes in pH or stability of solutionsof bupivacaine (0.25%, 0.5%, 0.75%) following sterilisation in glassampoules.

Chem. Abs. 97(25):222883 (1982) indicates that solutions of bupivacainein vials were stable to heat and light following sterilisation.

U.S. Pat. No. 5,505,922 discloses a combination of a local anestheticand lithium ions, to provide enhanced anesthetic activity. The lithiumions are described as a buffer. Among various possible additionalcomponents, it is suggested that pH buffers may be used to establish aphysiologically compatible pH range and to enhance the solubility of theanesthetic.

SUMMARY OF THE INVENTION

The present invention is based on the identification of a problemassociated with the provision of sterile aqueous solutions of an acidaddition salt of such carboxamide therapeutic agents, in a plasticscontainer, on the discovery of a reason for this problem, and also on asolution to it. The problem is that autoclaving causes a reduction inpH, and this may make the formulation more acidic than is suitable forthe intended use, particularly if a narrow pH range has been specified,for regulatory purposes. As shown by the evidence presented below, theproblem is caused by adsorption of the free base by the plastics, withthe release of acid. This problem is solved by the use of a buffer.

DESCRIPTION OF THE INVENTION

The problem that is addressed by the present invention has beenobserved, and will be described with reference to these materials by wayof illustration only, when the material of the container ispolypropylene and the therapeutic agent is levobupivacaine hydrochloridesalt. Polypropylene is often preferred for use in ampoules, vials orbags, e.g. of the type intended for infusion, but the invention may beequally applicable to other plastics materials, including otherpolyolefin polymers and copolymers.

The pKa of levobupivacaine is about 8.2 at 25° C. Typically, a solutionof levobupivacaine.HCl has a pH of 5-5.5. On autoclaving inpolypropylene ampoules, a pH drop is observed. It has been found that asmall amount (about 1%) of free base is adsorbed by the polypropyleneduring the autoclave cycle of an unbuffered solution, and thatadsorption in buffered solutions increases with pH. Thus, for example,buffer strength from 5 to 250 mM at pH 6 gives 30-40% adsorption, whilebuffering at 10 mM, pH 4, gave no pH change and limitation adsorption to0.2%.

The theory behind these observations is that the pKa of the amine groupin levobupivacaine drops as the temperature increases during theautoclaving cycle, providing free base in solution The hydrophobic freebase is adsorbed by the polypropylene, leaving residual HCl in solution,causing reduction of the pH. This reduction itself causes reprotonationof the remaining free base in solution, limiting the adsorption. Inbuffered systems of sufficient strength, the acid is removed by thebuffer, and the pH is maintained; in turn, this gives a constantsalt:free base ratio. This ratio will be of the order of 100:1 at 2 pHlimit below the pKa, and may be of the order of 50:50 at a pH equal tothe pKa. This ratio determines the amount of adsorption.

For the carboxamide-type anesthetic agents that are used in thisinvention, especial benefit may be seen when its concentration insolution is relatively high, e.g. at least 0.75% w/v. At such aconcentration, the pH drop observed on autoclaving is relatively great.However, a desire effect may be seen at lower concentrations, e.g. 0.25or 0.5% w/w.

Any suitable buffer may be used, and in particular a salt formed betweena weak acid and a strong base. Typical examples of such buffers arealkaline metal citrates, lactates and acetates. The amount of bufferthat is required can be very small, e.g. 5 to 100 mM.

Typically, the acid forming the acid addition salt of the carboamide isdifferent from that forming the buffer. It is preferably a hydrohalidesalt, and most preferably the hydrochloride.

The present invention is based on the following experimental evidence.

EXPERIMENTS

Levobupivacaine.HCl solutions in water for injection have a natural pHof 5.0-5.5. Autoclaving these solutions in the presence of polypropylene(PPE) causes the pH of the resulting solution to decrease by 1-2 pHunits.

A test solution was prepared by dissolving 1250 mg oflevobupivacaine.HCl in sodium chloride 0.5%, to provide a concentrationof 2.5 mg.ml⁻¹. A control solution of sodium chloride 0.9% was alsoprepared. The pH values of both the saline and the levobupivacaine.HClsolutions were measured, and the levobupivacaine.HCl solution wasanalysed by HPLC to determine the concentration of levobupivacaine.HClpresent

Levobupivacaine.HCl solution (200 ml) was transferred into two 250 mlautoclavable Schott bottles along with 20 grams of PPE (Appryl), and thelids sealed. A control bottle containing 200 ml of sodium chloride 0.9%was also prepared in a similar manner.

The control bottle containing the saline solution and one of the bottleswith the levobupivacaine.HCl solution were autoclaved at 121° C. for 20minutes. The second bottle containing levobupivacaine.HCl was left atambient temperature.

The pH and assay of each solution were determined after autoclaving. ThepH of the solution which was autoclaved in the presence ofPPE wasdecreased compared to the initial determination and the assay of eachsolution remained unchanged. This data showed that gross adsorption oflevobupivacaine to PPE was not occurring during autoclaving.

In order to determine if low levels of levobupivacaine were beingadsorbed to the PPE, the PPE was recovered from solution and a surfaceextraction process was employed. The PPE was separated from thesolutions by filtration through a sintered glass funnel and then washedwith 8×250 ml ofHPLC grade water to remove any solution from thesurface. The PPE was then dried for 65 hours in a vacuum oven,containing a tray of silica gel as a desiccant, at 70° C. Once dried,the PPE was weighed and transferred into a clean 250 ml Schott bottle.HPLC grade dichloromethane (200 ml) was added and the lid sealed. After48 h of extraction time, the PPE was removed by filtration. Thedichloromethane was transferred to a round-bottom flask and removed byrotary evaporation, and the residue was dissolved in and diluted to 10ml with tetrahydrofuran (THF)

A standard solution ofbupivacaine free base (1 mg ml³¹) in THF wasprepared. The level of levobupivacaine base in solution was determinedby chromatography against the standard and from this the level ofadsorption was calculated to be 0.97%.

These experiments show that there is interaction between polypropyleneand levobupivacaine.HCl during autoclaving in aqueous solution.Levobupivacaine adsorbs on to the plastic to a small extent as the freebase, which leaves a slight excess of HCl in solution. This ismanifested as a decrease in pH.

What is claimed is:
 1. A plastic container containing a sterile aqueoussolution of an acid addition salt of a1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, wherein thesolution is buffered to pH 3-6.
 2. The container according to claim 1,wherein the container is an ampoule or vial.
 3. The container accordingto claim 1, wherein the container is a bag.
 4. The container accordingto claim 1, wherein the material of the container is polypropylene. 5.The container according to claim 1, wherein the salt is a hydrohalide.6. The container according to claim 5, wherein the salt is thehydrochloride.
 7. The container according to claim 1, wherein thecarboxamide is bupivacaine or levobupivacaine.
 8. The containeraccording to claim 1, wherein the solution comprises at least 0.75% w/vof the carboxanide.
 9. The container according to claim 1, wherein thesolution is buffered to pH 3.5-5.
 10. The container according to claim1, wherein the buffer is citrate.
 11. The container according to claim2, wherein the material of the container is polypropylene.
 12. Thecontainer according to claim 3, wherein the material of the container ispolypropylene.